The chromatin-binding domain of Ki-67 together with p53 protects human chromosomes from mitotic damage

Garwain, Osama; Sun, Xiaoming; Iyer, Divya Ramalingam; Li, Rui; Zhu, Lihua Julie; Kaufman, Paul D.

doi:10.1073/pnas.2021998118

Cited by 10 publications

(6 citation statements)

References 79 publications

(114 reference statements)

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“…We cannot link these genes to initial Ki-67 binding or Ki-67 biology. A similar result was obtained in a recent study that also employed auxin-mediated Ki-67-AID depletion in HCT116 cells (Garwain et al , 2020).…”

Section: Resultssupporting

confidence: 89%

“…We then asked whether Ki-67 contributes directly to the transcriptional repression of these genes. Several studies have found changes in gene activity upon Ki-67 loss (Garwain et al , 2020; Mrouj et al , 2021; Sobecki et al , 2016; Sun et al , 2017), but none could attribute this to direct effects, in part because the binding pattern of Ki-67 was not known. We therefore generated RNA-seq data in the HCT116 Ki-67-AID cells.…”

Section: Resultsmentioning

confidence: 99%

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Dynamic chromosomal interactions and control of heterochromatin positioning by Ki-67

Schaik

Manzo

Vouzas

et al. 2021

Preprint

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Ki67 forms a protective layer around mitotic chromosomes and is involved in genome positioning around nucleoli during interphase. However, a lack of genomic interaction maps has hampered a detailed understanding of the role of Ki67 in chromatin organization. We used pA-DamID to map genome-Ki67 interactions in three human cell lines and throughout the cell cycle. In mitosis, Ki67 shows a surprising preference for the distal 15-30 Mb of each chromosome. Early in interphase, when Ki67 is present in pre-nucleolar bodies, this is replaced by a pattern of large domains that overlaps with late-replicating DNA, which gradually shifts towards small chromosomes. Nucleolar perturbations indicate that these cell cycle dynamics correspond to nucleolar maturation during interphase. Furthermore, Ki67 competes with the nuclear lamina for interaction with late-replicating DNA, and controls replication timing at (peri)centromeric regions. Together, these results reveal a highly dynamic choreography of genome interactions and roles for Ki67 in genome organization.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Dynamic chromosomal interactions and control of heterochromatin positioning by Ki-67

Schaik

Manzo

Vouzas

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…We cannot link these genes to initial Ki‐67 binding or Ki‐67 biology. A similar result was obtained in a recent study that also employed auxin‐mediated Ki‐67‐AID depletion in HCT116 cells (Garwain et al , 2020).…”

Section: Resultssupporting

confidence: 87%

“…We then asked whether Ki‐67 contributes directly to the transcriptional repression of these genes. Several studies have found changes in gene activity upon Ki‐67 loss (Sobecki et al , 2016; Sun et al , 2017; Garwain et al , 2020; Mrouj et al , 2021), but none could attribute this to direct effects, in part because the binding pattern of Ki‐67 was not known. We therefore generated RNA‐seq data in the HCT116 Ki‐67‐AID cells.…”

Section: Resultsmentioning

confidence: 99%

Dynamic chromosomal interactions and control of heterochromatin positioning by Ki‐67

et al. 2022

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Ki-67 is a chromatin-associated protein with a dynamic distribution pattern throughout the cell cycle and is thought to be involved in chromatin organization. The lack of genomic interaction maps has hampered a detailed understanding of its roles, particularly during interphase. By pA-DamID mapping in human cell lines, we find that Ki-67 associates with large genomic domains that overlap mostly with late-replicating regions. Early in interphase, when Ki-67 is present in pre-nucleolar bodies, it interacts with these domains on all chromosomes. However, later in interphase, when Ki-67 is confined to nucleoli, it shows a striking shift toward small chromosomes. Nucleolar perturbations indicate that these cell cycle dynamics correspond to nucleolar maturation during interphase, and suggest that nucleolar sequestration of Ki-67 limits its interactions with larger chromosomes. Furthermore, we demonstrate that Ki-67 does not detectably control chromatinchromatin interactions during interphase, but it competes with the nuclear lamina for interaction with late-replicating DNA, and it controls replication timing of (peri)centromeric regions. Together, these results reveal a highly dynamic choreography of genome interactions and roles for Ki-67 in heterochromatin organization.

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“…In our post‐traumatic rabbit TMJ OA model, our RNA‐seq analyses reveal for the first time changes in gene expression levels of cell cycle process within each tissue group. Upon further investigation, we found that genes related to the cell cycle process were downregulated in the injured SZ group relative to healthy SZ tissues, including MKI67 28,29 and PCNA 30 . On the other hand, genes related to cell cycle were significantly upregulated in the injured CC group compared to healthy CC group (Figure 6A).…”

Section: Resultsmentioning

confidence: 95%

Bulk RNA‐seq analyses of mandibular condylar cartilage in a post‐traumatic TMJ osteoarthritis rabbit model

Tosa

Ruscitto

Wang

et al. 2023

Orthod Craniofacial Res

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ObjectiveThe temporomandibular joint (TMJ) is anatomically comprised of the mandibular condylar cartilage (CC) lined with fibrocartilaginous superficial zone and is crucial for eating and dental occlusion. TMJ osteoarthritis (OA) leads to pain, joint dysfunction and permanent loss of cartilage tissue. However, there are no drugs clinically available that ameliorate OA and little is known about global profiles of genes that contribute to TMJ OA. Furthermore, animal models that recapitulate the complexity of signalling pathways contributing to OA pathogenesis are crucial for designing novel biologics that thwart OA progression. We have previously developed a New Zealand white rabbit TMJ injury model that demonstrates CC degeneration. Here, we performed genome‐wide profiling to identify new signalling pathways critical for cellular functions during OA pathology.Materials and MethodsTemporomandibular joint OA was surgically induced in New Zealand white rabbits. Three months following injury, we performed global gene expression profiling of the TMJ condyle. RNA samples from TMJ condyles were subjected to sequencing. After raw RNA‐seq data were mapped to relevant genomes, differential expression was analysed with DESeq2. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted.Results/ConclusionsOur study revealed multiple pathways altered during TMJ OA induction including the Wnt, Notch and PI3K‐Akt signalling pathways. We demonstrate an animal model that recapitulates the complexity of the cues and signals underlying TMJ OA pathogenesis, which is essential for developing and testing novel pharmacologic agents to treat OA.

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The chromatin-binding domain of Ki-67 together with p53 protects human chromosomes from mitotic damage

Cited by 10 publications

References 79 publications

Dynamic chromosomal interactions and control of heterochromatin positioning by Ki-67

Dynamic chromosomal interactions and control of heterochromatin positioning by Ki-67

Dynamic chromosomal interactions and control of heterochromatin positioning by Ki‐67

Bulk RNA‐seq analyses of mandibular condylar cartilage in a post‐traumatic TMJ osteoarthritis rabbit model

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